Injectable PEG-like Conjugate for Sustained Delivery of a Peptide Drug for Type 2 Diabetes Treatment

用于持续递送肽药物治疗 2 型糖尿病的可注射 PEG 样缀合物

• 批准号: 10314066
• 负责人: Ashutosh Chilkoti
• 金额: $ 46.52万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-10 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314066
• 关键词: Address; Age; Allergic Reaction; American; Antibodies; Behavior; Binding; Biological Availability; Biological Products; Blood Circulation; Blood Glucose; Clinical; Data; Diabetes Mellitus; Diabetic mouse; Dose; Drug Delivery Systems; Drug Industry; Drug Kinetics; FDA approved; Formulation; GLP-I receptor; Glucagon; Glycosylated Hemoglobin; Goals; Half-Life; Hemoglobin concentration result; Hour; Individual; Injectable; Injections; Islet Cell; Islets of Langerhans; Kidney; Kinetics; Length; Life; Medicine; Methacrylates; Methodology; Methyl Ethers; Molecular Weight; Non-Insulin-Dependent Diabetes Mellitus; Oligonucleotides; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase III Clinical Trials; Phase Transition; Plasma; Polyethylene Glycols; Polymers; Problem Solving; Property; Proteins; Research; Reticuloendothelial System; Sampling; Side; Site; Skin; Specificity; Structure; System; Technology; Temperature; Testing; Therapeutic; Transition Temperature; United States National Institutes of Health; Vertebral column; blood glucose regulation; copolymer; design; diabetic; drug candidate; drug efficacy; drug market; drug withdrawal; ethylene glycol; immunogenicity; improved; in vitro activity; in vivo; insulin secretion; islet; new technology; next generation; peptide drug; pharmacokinetics and pharmacodynamics; side effect; subcutaneous

ABSTRACT The objective of this NIH R01 proposal is to develop a non-immunogenic, injectable depot of a PEG-like conjugate of a peptide drug for systemic drug delivery. This proposal is motivated by the fact that many peptide and protein drugs have a short plasma half-life on the order of minutes to a few hours. PEGylation —the conjugation of polyethylene glycol (PEG) moieties to biologics— is commonly used to overcome these limitations. Unfortunately, PEG is antigenic, which has led to the early termination of a Phase III clinical trial of a PEGylated drug candidate and withdrawal of several PEGylated drugs from the market because of severe allergic reactions in some patients. These problems have been traced to circulating anti-PEG antibodies that are found even in individuals who have not previously received a PEGylated drug. Furthermore, the improvement in pharmacokinetics (PK) and pharmacodynamics (PD) conferred by PEG and its branched derivatives are now at an asymptote. This proposal addresses the urgent, unmet need to develop the next-generation of PEGylation that overcomes these limitations. We hypothesize that we can solve the immunogenicity problem of PEG conjugates and further extend the half-life of PEG conjugates by a next generation PEG-like “stealth” polymer, poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) that presents short oligomeric ethylene glycol (OEG) side-chains on a backbone. This hypothesis is validated by our preliminary data that shows that reactivity towards patient-derived anti-PEG antibodies is eliminated by shortening the OEG side-chain length to ≤3 without compromising PK or PD, and that a copolymer with a mixture of two and three EG long side-chains also allows POEGMA to reversibly transition from a solution into an insoluble coacervate between 25-37 ºC, thereby enabling the creation of a sustained release depot. We will demonstrate the utility of this non-immunogenic, injectable drug depot by synthesizing POEGMA conjugates of exendin —a potent but short-acting clinically approved peptide drug for type 2 diabetes— and show that exendin-POEGMA conjugates are pharmacologically active, form a depot upon subcutaneous (s.c.) injection in diabetic mice, show zero-order release kinetics into the bloodstream from the depot, leading to sustained glucose control in diabetic (db/db) mice, while simultaneously eliminating PEG immunogenicity and antigenicity. The overall significance of this research is that it will solve the problem of PEG antigenicity and will also improve upon the PK and PD of PEG conjugates by creating an injectable PEG conjugate that forms a s.c. depot with sustained release of the drug. By doing so, it will breathe new life into an established drug delivery technology that is now beginning to show its age. More specifically, it will also enable improved management of type diabetes for the ~30 million Americans who are diabetic. Because the POEGMA conjugate technology can likely be applied to the many therapeutics —beyond exendin— that have a short plasma half-life and where anti-PEG antibodies are of concern, it has the potential to have broad impact.

抽象的 该NIH R01提案的目的是开发一种非免疫原性的，可注射的矿床 肽药物的结合物用于全身药物递送。该提议是由于许多肽的动机 蛋白质药物的血浆半衰期在几分钟到几个小时的时间内。 Pegylation- 聚乙烯乙二醇（PEG）部分与生物制剂的共轭 - 通常用于克服这些 限制。不幸的是，PEG是抗原，这导致了A期III期临床试验的早期终止 由于严重 某些患者的过敏反应。这些问题已被追溯到循环抗PEG抗体 即使是在以前没有接受过类药物的人中发现的。此外，改进 PEG及其分支衍生物赋予的药代动力学（PK）和药效学（PD）现在位于 渐近线。该提案解决了发展下一代的紧急，未满足的需求 这克服了这些局限性。我们假设我们可以解决PEG的免疫原性问题 结合并进一步扩大了下一代钉子般的“隐身”聚合物的钉子的半衰期， 聚[寡素（乙二醇）甲基乙烯甲酸酯（Poegma），呈现短寡聚乙二醇 （OEG）骨架上的侧链。该假设通过我们的初步数据验证，该数据表明反应性 通过将OEG的侧链长度缩短到没有 妥协的PK或PD，并且具有两个和三个混合物的共聚物，例如长侧链也可以 在25-37ºC之间从溶液中转变为不可差的塞子的poegma，从而实现了 创建持续的释放押金。我们将证明这种非免疫原性，可注射的效用 药物库通过合成脱发素的poegma缀合物 - 潜在但临床批准的短暂作用 用于2型糖尿病的肽药物 - 表明脱落蛋白 - 斑点结合物具有药物活性， 在糖尿病小鼠的皮下（S.C.）注射下形成一个仓库，显示零级释放动力学 来自仓库的血液，导致糖尿病（dB/db）小鼠的持续葡萄糖控制，同时进行 消除PEG免疫原性和抗原性。这项研究的总体意义是它将解决 PEG抗原性问题，也将通过创建一个PEG共轭的PK和PD来改善 形成S.C.的注射钉共轭物仓库随着药物的持续释放。这样，它将呼吸 新的生命成为已建立的药物输送技术，该技术现在开始显示其年龄。更具体地说，它 还将为糖尿病患者约3000万美国人改善糖尿病的治疗。因为 Poegma共轭技术可能可以应用于许多治疗剂（Beyond Exendin） 具有短血浆半衰期和抗PEG抗体的关注，它具有广泛的潜力 影响。